Antagonists of gonadotropin releasing hormone

ABSTRACT

There are disclosed compounds of formula (I) ##STR1## and pharmaceutically acceptable salts thereof which are useful as antagonists of GnRH and as such may be useful for the treatment of a variety of sex-hormone related and other conditions in both men and women.

This application claims priority from Provisional Application No.60/080,402 filed Apr. 2, 1998.

BACKGROUND OF THE INVENTION

The gonadotropin-releasing hormone (GnRH), also referred to asluteinizing hormone-releasing hormone (LHRH), is a decapeptide thatplays a key role in human reproduction. The hormone is released from thehypothalamus and acts on the pituitary gland to stimulate thebiosynthesis and secretion of luteinizing hormone (LH) andfollicle-stimulating hormone (FSH). LH released from the pituitary glandis primarily responsible for the regulation of gonadal steroidproduction in both sexes, whereas FSH regulates spermatogenesis in malesand follicular development in females. GnRH agonists and antagonistshave proven effective in the treatment of certain conditions whichrequire inhibition of LH/FSH release. In particular, GnRH-basedtherapies have proven effective in the treatment of endometriosis,uterine fibroids, polycystic ovarian disease, precocious puberty andseveral gonadal steroid-dependent neoplasia, most notably cancers of theprostate, breast and ovary. GnRH agonists and antagonists have also beenutilized in various assisted fertilization techniques and have beeninvestigated as a potential contraceptive in both men and women. Theyhave also shown possible utility in the treatment of pituitarygonadotrophe adenomas, sleep disorders such as sleep apnea, irritablebowel syndrome, premenstrual syndrome, benign prostatic hyperplasia,hirsutism, as an adjunct to growth hormone therapy in growth hormonedeficient children, and in murine models of lupus. The compounds of theinvention may also be used in combination with bisphosphonates(bisphosphonic acids) and other agents, such as growth hormonesecretagogues, for the treatment and the prevention of disturbances ofcalcium, phosphate and bone metabolism, in particular, for theprevention of bone loss during therapy with the GnRH antagonist, and incombination with estrogens, progesterones, antiestrogens, antiprogestinsand/or androgens for the prevention or treatment of bone loss orhypogonadal symptoms such as hot flashes during therapy with the GnRHantagonist.

Additionally, a compound of the present invention may be co-administeredwith a 5a-reductase 2 inhibitor, such as finasteride or epristeride; a5a-reductase 1 inhibitor such as 4,7b-dimethyl-4-aza-5a-cholestan-3-one,3-oxo-4-aza-4,7b-dimethyl-16b-(4-chlorophenoxy)-5a-androstane, and3-oxo-4-aza-4,7b-dimethyl-16b-(phenoxy)-5a-androstane as disclosed in WO93/23420 and WO 95/11254; dual inhibitors of 5a-reductase 1 and5a-reductase 2 such as3-oxo-4-aza-17b-(2,5-trifluoromethylphenyl-carbamoyl)-5a-androstane asdisclosed in WO 95/07927; antiandrogens such as flutamide, casodex andcyproterone acetate, and alpha-1 blockers such as prazosin, terazosin,doxazosin, tamsulosin, and alfuzosin.

Further, a compound of the present invention may be used in combinationwith growth hormone, growth hormone releasing hormone or growth hormonesecretagogues, to delay puberty in growth hormone deficient children,which will allow them to continue to gain height before fusion of theepiphyses and cessation of growth at puberty.

Further, a compound of the present invention may be used in combinationor co-administered with a compound having luteinizing hormone releasingactivity such as a peptide or natural hormone or analog thereof. Suchpeptide compounds include leuprorelin, gonadorelin, buserelin,triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterlin andrecirelin.

Additionally, a compound of the present invention may be used asdescribed in U.S. Pat. No. 5,824,286 which discloses the administrationof peptide GnRH antagonists such as Antide and azaline B topremenopausal women to enhance the readability of mammographic filmrelative to a mammogram effected in the absence of the administration.

Current GnRH antagonists are GnRH-like decapeptides which are generallyadministered intravenously or subcutaneously presumably because ofnegligible oral activity. These have amino acid substitutions usually atpositions one, two, three, six and ten.

Non-peptide GnRH antagonists offer the possible advantage of oraladminstration. Non-peptide GnRH antagonists have been described inEuropean Application 0 219 292 and in De, B. et al., J. Med. Chem., 32,2036-2038 (1989), in WO 95/28405, WO 95/29900 and EP 0679642 all toTakeda Chemical Industries, Ltd.

Substituted indoles known in the art include those described in thefollowing patents and patent applications. U.S. Pat. No. 5,030,640discloses alpha-heterocyclic ethanol aminoalkyl indoles which are potentβ-agonists. U.S. Pat. No. 4,544,663 discloses indolamine derivativeswhich are allegedly useful as male anti-fertility agents. WO 90/05721discloses alpha-amino-indole-3-acetic acids useful as anti-diabetic,anti-obesity and anti-atherosclerotic agents. French patent 2,181,559discloses indole derivatives with sedative, neuroleptic, analgesic,hypotensive, antiserotonin and adrenolytic activity. Belgian patent879381 discloses 3-aminoalkyl-1H-indole-5-thioamide and carboxamidederivatives as cardiovascular agents used to treat hypertension,Raynaud's disease and migraine. U.S. Pat. Nos. 5,756,507, 5,780,437 and5,849,764 also disclose substituted arylindoles as non-peptideantagonists of GnRH.

SUMMARY OF THE INVENTION

The present invention relates to compounds which are non-peptideantagonists of GnRH which can be used to treat a variety of sex-hormonerelated conditions in men and women, to methods for their preparation,and to methods and pharmaceutical compositions containing said compoundsfor use in mammals.

Because of their activity as antagonists of the hormone GnRH, thecompounds of the present invention are useful to treat a variety ofsex-hormone related conditions in both men and women. These conditionsinclude endometriosis, uterine fibroids, polycystic ovarian disease,hirsutism, precocious puberty, gonadal steroid-dependent neoplasias suchas cancers of the prostate, breast and ovary, gonadotrophe pituitaryadenomas, sleep apnea, irritable bowel syndrome, premenstrual syndromeand benign prostatic hypertophy. They are also useful as an adjunct totreatment of growth hormone deficiency and short stature, and for thetreatment of systemic lupus erythematosis. Further, the compounds of theinvention may be useful in in vitro fertilization and as contraceptives.The compounds may also be useful in combination with androgens,estrogens, progesterones, antiestrogens and antiprogestogens for thetreatment of endometriosis, fibroids and in contraception. They may alsobe useful in combination with testosterone or other androgens orantiprogestogens in men as a contraceptive. The compounds may also beused in combination with an angiotensin-converting enzyme inhibitor suchas Enalapril or Captopril, an angiotensin II-receptor antagonist such asLosartan or a renin inhibitor for the treatment of uterine fibroids.Additionally, the compounds of the invention may also be used incombination with bisphosphonates (bisphosphonic acids) and other agents,for the treatment and the prevention of disturbances of calcium,phosphate and bone metabolism, in particular, for the prevention of boneloss during therapy with the GnRH antagonist, and in combination withestrogens, progesterones and/or androgens for the prevention ortreatment of bone loss or hypogonadal symptoms such as hot flashesduring therapy with the GnRH antagonist.

Additionally, a compound of the present invention may be co-administeredwith a 5a-reductase 2 inhibitor, such as finasteride or epristeride; a5a-reductase 1 inhibitor such as 4,7b-dimethyl-4-aza-5a-cholestan-3-one,3-oxo-4-aza-4,7b-dimethyl-16b-(4-chlorophenoxy)-5a-androstane, and3-oxo-4-aza-4,7b-dimethyl-16b-(phenoxy)-5a-androstane as disclosed in WO93/23420 and WO 95/11254; dual inhibitors of 5a-reductase 1 and5a-reductase 2 such as3-oxo-4-aza-17b-(2,5-trifluoromethylphenyl-carbamoyl)-5a-androstane asdisclosed in WO 95/07927; antiandrogens such as flutamide, casodex andcyproterone acetate, and alpha-1 blockers such as prazosin, terazosin,doxazosin, tamsulosin, and alfuzosin.

Further, a compound of the present invention may be used in combinationwith growth hormone, growth hormone releasing hormone or growth hormonesecretagogues, to delay puberty in growth hormone deficient children,which will allow them to continue to gain height before fusion of theepiphyses and cessation of growth at puberty.

Further, a compound of the present invention may be used in combinationor co-administered with a compound having luteinizing hormone releasingactivity such as a peptide or natural hormone or analog thereof. Suchpeptide compounds include leuprorelin, gonadorelin, buserelin,triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterlin andrecirelin.

Additionally, a compound of the present invention may be used asdescribed in U.S. Pat. No. 5,824,286 which discloses the administrationof peptide GnRH antagonists such as Antide and azaline B topremenopausal women to enhance the readability of mammographic filmrelative to a mammogram effected in the absence of the administration.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of the general formula##STR2## wherein A is C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, C₃ -C₇cycloalkyl, substituted C₃ -C₇ cycloalkyl, C₃ -C₆ alkenyl, substitutedC₃ -C₆ alkenyl, C₃ -C₆ alkynyl, substituted C₃ -C₆ alkynyl, C₁ -C₆alkoxy, or C₀ -C₅ alkyl-S(O)_(n) -C₀ -C₅ alkyl, C₀ -C₅ alkyl-O-C₀ -C₅alkyl, C₀ -C₅ alkyl-NR₁₈ -C₀ -C₅ alkyl where R₁₈ and the C₀ -C₅ alkylcan be joined to form a ring, ##STR3## or a single bond; R₀ is hydrogen,C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, wherein the substituents are asdefined below; aryl, substituted aryl, aralkyl or substituted aralkyl,wherein the substituents are as defined for R₃, R₄ and R₅ ;

R₁ is ##STR4## wherein: Y is B, C or a bond;

B is O, S(O)_(n), C(O), NR₁₈ or C(R₁₁ R₁₂)_(p)

C is B(CH₂)_(p) --;

R₂ is hydrogen, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, aralkyl,substituted aralkyl, aryl, substituted aryl, alkyl --OR₁₁, C₁ -C₆ (NR₁₁R₁₂), C₁ -C₆ (CONR₁₁ R₁₂) or C(NR₁₁ R₁₂)NH;

R₂ and A taken together form a ring of 5-7 atoms;

R₃, R₄ and R₅ are independently hydrogen, C₁ -C₆ alkyl, substituted C₁-C₆ alkyl, C₂ -C₆ alkenyl, substituted C₂ -C₆ alkenyl, CN, nitro, C₁ -C₃perfluoroalkyl, C₁ -C₃ perfluoroalkoxy, aryl, substituted aryl, aralkyl,substituted aralkyl, R₁₁ O(CH₂)_(p) --, R₁₁ C(O)O(CH₂)_(p) --, R₁₁OC(O)(CH₂)_(p) --, --(CH₂)_(p) S(O)_(n) R₁₇, --(CH₂)_(p) C(O)NR₁₁ R₁₂ orhalogen; wherein R₁₇ is hydrogen, C₁ -C₆ alkyl, C₁ -C₃ perfluoroalkyl,aryl or substituted aryl;

R₃ and R₄ taken together form a carbocyclic ring of 3-7 carbon atoms ora heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;

R₆ is hydrogen, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, aryl,substituted aryl, C₁ -C₃ perfluoroalkyl, CN, NO₂, halogen, R₁₁O(CH₂)_(p) --, NR₁₂ C(O)R₁₁, NR₁₂ C(O)NR₁₁ R₁₂ or SO_(n) R₁₁ ;

R₇ is hydrogen, C₁ -C₆ alkyl, or substituted C₁ -C₆ alkyl, unless X ishydrogen or halogen, then R₇ is absent;

R₈ is hydrogen, C(O)OR₉, C(O)NR₁₁ R₁₂, NR₁₁ R₁₂, C(O)R₁₁, NR₁₂ C(O)R₁₁,NR₁₂ C(O)NR₁₁ R₁₂, NR₁₂ S(O)₂ R₁₁, NR₁₂ S(O)₂ NR₁₁ R₁₂, OC(O)R₁₁,OC(O)NR₁₁ R₁₂, OR₁₁, SO_(n) R₁₁, S(O)_(n) NR₁₁ R₁₂, C₁ -C₆ alkyl orsubstituted C₁ -C₆ alkyl, unless X is hydrogen or halogen, then R₈ isabsent; or

R₇ and R₈ taken together form a carbocyclic ring of 3-7 atoms;

R₉ and R_(9a) are independently hydrogen, C₁ -C₆ alkyl, substituted C₁-C₆ alkyl; aryl or substituted aryl, aralkyl or substituted aralkyl whenm≠0; or

R₉ and R_(9a) taken together form a carbocyclic ring of 3-7 atoms or##STR5## when m≠0; R₉ and A taken together form a heterocyclic ringcontaining 3-7 carbon atoms and one or more heteroatoms when m≠0; or

R₁₀ and R_(10a) are independently hydrogen, C₁ -C₆ alkyl, substituted C₁-C₆ alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl; or

R₁₀ and R_(10a) taken together form a carbocyclic ring of 3-7 atoms or##STR6## R₉ and R₁₀ taken together form a carbocyclic ring of 3-7 carbonatoms or a heterocyclic ring containing one or more heteroatoms whenm≠0; or

R₉ and R₂ taken together form a heterocyclic ring containing 3-7 carbonatoms and one or more heteroatoms when m≠0; or

R₁₀ and R₂ taken together form a heterocyclic ring containing 3-7 carbonatoms and one or more heteroatoms;

R₁₀ and A taken together form a heterocyclic ring containing 3-7 carbonatoms and one or more heteroatoms; or

R₁₁ and R₁₂ are independently hydrogen, C₁ -C₆ alkyl, substituted C₁ -C₆alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, acarbocyclic ring of 3-7 atoms or a substituted carbocyclic ringcontaining 3-7 atoms;

R₁₁ and R₁₂ taken together can form an optionally substituted ring of3-7 atoms;

R₁₃ is hydrogen, OH, NR₇ R₈, NR₁₁ SO₂ (C₁ -C₆ alkyl), NR₁₁ SO₂(substituted C₁ -C₆ alkyl), NR₁₁ SO₂ (aryl), NR₁₁ SO₂ (substitutedaryl), NR₁₁ SO₂ (C₁ -C₃ perfluoroalkyl); SO₂ NR₁₁ (C₁ -C₆ alkyl), SO₂NR₁₁ (substituted C₁ -C₆ alkyl), SO₂ NR₁₁ (aryl), SO₂ NR₁₁ (substitutedaryl), SO₂ NR₁₁ (C₁ -C₃ perfluoroalkyl); SO₂ NR₁₁ (C(O)C₁ -C₆ alkyl);SO₂ NR₁₁ (C(O)-substituted C₁ -C₆ alkyl); SO₂ NR₁₁ (C(O)-aryl); SO₂ NR₁₁(C(O)-substituted aryl); S(O)_(n) (C₁ -C₆ alkyl); S(O)_(n) (substitutedC₁ -C₆ alkyl), S(O)_(n) (aryl), S(O)_(n) (substituted aryl), C₁ -C₃perfluoroalkyl, C₁ -C₃ perfluoroalkoxy, C₁ -C₆ alkoxy, substituted C₁-C₆ alkoxy, COOH, halogen, NO₂ or CN;

R₁₄ and R₁₅ are independently hydrogen, C₁ -C₆ alkyl, substituted C₁ -C₆alkyl, C₂ -C₆ alkenyl, substituted C₂ -C₆ alkenyl, CN, nitro, C₁ -C₃perfluoroalkyl, C₁ -C₃ perfluoroalkoxy, aryl, substituted aryl, aralkyl,substituted aralkyl, R₁₁ O(CH₂)_(p) --, R₁₁ C(O)O(CH₂)_(p) --, R₁₁OC(O)(CH₂)_(p) --, --(CH₂)_(p) S(O)_(n) R₁₇, --(CH₂)_(p) C(O)NR₁₁ R₁₂ orhalogen; wherein R₁₇ is hydrogen, C₁ -C₆ alkyl, C₁ -C₃ perfluoroalkyl,aryl or substituted aryl;

R₁₆ is hydrogen, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, or N(R₁₁ R₁₂);

R₁₈ is hydrogen, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, C(O)OR₉,C(O)NR₁₁ R₁₂, C(O)R₁₁, S(O)_(n) R₁₁ ;

X is hydrogen, halogen, N, O, S(O)_(n), C(O), (CR₁₁ R₁₂)_(p) ; C₂ -C₆alkenyl, substituted C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, or substituted C₂-C₆ alkynyl; when X is hydrogen or halogen, R₇ and R₈ are absent; when Xis O, S(O)n, C(O), or CR₁₁ R₁₂ only R₇ or R₈ is possible;

m is 0-3;

n is 0-2;

p is 0-4; and

the alkyl, cycloalkyl, alkenyl and alkynyl substituents are selectedfrom C₁ -C₆ alkyl, C₃ -C₇ cycloalkyl, aryl, substituted aryl, aralkyl,substituted aralkyl, hydroxy, oxo, cyano, C₁ -C₆ alkoxy, fluoro,C(O)OR₁₁, aryl C₁ -C₃ alkoxy, substituted aryl C₁ -C₃ alkoxy, and thearyl substituents are as defined for R₃, R₄ and R₅ ;

or a pharmaceutically acceptable addition salt and/or hydrate thereof,or where applicable, a geometric or optical isomer or racemic mixturethereof.

Unless otherwise stated or indicated, the following definitions shallapply throughout the specification and claims.

When any variable (e.g., aryl, heterocycle, R₁, etc.) occurs more thanone time in any constituent or in formula I, its definition on eachoccurrence is independent of its definition at every other occurrence.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

The term "alkyl" is intended to include both branched- andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, e.g., methyl (Me), ethyl (Et), propyl,butyl, pentyl, hexyl, heptyl, octyl, nonanyl, decyl, undecyl, dodecyl,and the isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu),sec-butyl (s-Bu), tert-butyl (t-Bu), isopentane, isohexane, etc.

The term "aryl" includes phenyl and naphthyl. In a preferred embodiment,aryl is phenyl.

The term "halogen" or "halo" is intended to include fluorine, chlorine,bromine and iodine.

The term "heterocycle" or "heterocyclic ring" is defined by allnon-aromatic, heterocyclic rings of 3-7 atoms containing 1-3 heteroatomsselected from N, O, and S, such as oxirane, oxetane, tetrahydrofuran,tetrahydropyran, pyrrolidine, piperidine, tetrahydropyridine,tetrahydropyrimidine, tetrahydrothiophene, tetrahydrothiopyran,morpholine, hydantoin, valerolactam, pyrrolidinone, and the like.

As used herein, the term "composition" is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts

In addition, it is well known to those skilled in the art that many ofthe foregoing heterocyclic groups can exist in more than one tautomericform. It is intended that all such tautomers be included within theambit of this invention.

The optical isomeric forms, that is mixtures of enantiomers, e.g.,racemates, or diastereomers as well as individual enantiomers ordiastereomers of the instant compound are included. These individualenantiomers are commonly designated according to the optical rotationthey effect by the symbols (+) and (-), (L) and (D), (1) and (d) orcombinations thereof. These isomers may also be designated according totheir absolute spatial configuration by (S) and (R), which stands forsinister and rectus, respectively.

The individual optical isomers may be prepared using conventionalresolution procedures, e.g., treatment with an appropriate opticallyactive acid, separating the diastereomers and then recovering thedesired isomer. In addition, the individual optical isomers may beprepared by asymmetric synthesis.

Additionally, a given chemical formula or name shall encompasspharmaceutically acceptable addition salts thereof and solvates thereof,such as hydrates.

The compounds of the present invention, while effective themselves, maybe formulated and administered in the form of their pharmaceuticallyacceptable addition salts for purposes of stability, convenience ofcrystallization, increased solubility and other desirable properties.

The compounds of the present invention may be administered in the formof pharmaceutically acceptable salts. The term "pharmaceuticallyacceptable salt" is intended to include all acceptable salts. Examplesof acid salts are hydrochloric, nitric, sulfuric, phosphoric, formic,acetic, trifluoroacetic, propionic, maleic, succinic, malonic,methanesulfonic, benzenesulfonic and the like which can be used as adosage form for modifying the solubility or hydrolysis characteristicsor can be used in sustained release or prodrug formulations. Dependingon the particular functionality of the compound of the presentinvention, pharmaceutically acceptable salts of the compounds of thisinvention include those formed from cations such as sodium, potassium,aluminum, calcium, lithium, magnesium, zinc, and from bases such asammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine,ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine,diethanolamine, procaine, N-benzylphenethylamine, diethylamine,piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammoniumhydroxide. These salts may be prepared by standard procedures, e.g. byreacting a free acid with a suitable organic or inorganic base, oralternatively by reacting a free base with a suitable organic orinorganic acid.

Also, in the case of an acid (--COOH) or alcohol group being present,pharmaceutically acceptable esters can be employed, e.g. methyl, ethyl,butyl, acetate, maleate, pivaloyloxymethyl, and the like, and thoseesters known in the art for modifying solubility or hydrolysischaracteristics for use as sustained release or prodrug formulations.

The compounds of the present invention may have chiral centers otherthan those centers whose stereochemistry is depicted in formula I, andtherefore may occur as racemates, racemic mixtures and as individualenantiomers or diastereomers, with all such isomeric forms beingincluded in the present invention as well as mixtures thereof.Furthermore, some of the crystalline forms for compounds of the presentinvention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe instant invention may form solvates with water or common organicsolvents. Such solvates are encompassed within the scope of thisinvention.

The compounds of the invention are prepared according to the followingreaction schemes. All of the substituents are as defined above unlessindicated otherwise. ##STR7##

A preferred method for the synthesis of the substituted tryptaminesdescribed in this invention utilizes a palladium-catalyzed crosscoupling reaction as a key step as shown in Scheme A. This 7-azaindolesynthesis involves the reaction of a suitably functionalized3-iodo-2-aminopyridine (1) with substituted acetylenes such as 2 in thepresence of a base like sodium carbonate, lithium chloride, and apalladium catalyst such as (dppf)PdCl₂.CH₂ Cl₂. The reaction isconducted in an inert organic solvent such as dimethylformamide atelevated temperatures, for instance at 100° C., and the reaction isconducted for a period of about 30 minutes to about 24 hours. A standardworkup and isolation affords the substituted isomeric indole derivatives3 and 4, and the isomer of general formula 3 is the preferred isomer.The acetylene utilized in this reaction may be a terminal acetylene (2a)or be optionally substituted on the terminal carbon atom with asubstituent Z (2b, 2c). The substituent abbreviated PG₁ indicates analcohol protecting group such as a benzyl ether, tert-butyl ether or thelike. The nature of the Z substituent determines the distribution of the7-azaindole isomers (3 and 4) produced in the reaction. For example, ifthe substituent Z on the acetylene is a hydrogen atom then the isomer 4ais the major product of the reaction. When the substituent Z is chosento be a substituted silyl group such as trimethylsilyl, triethylsilyl(as shown), or the like, then isomer 3b is formed almost exclusively.When Z is a substituted aryl group, then both isomers 3c and 4c may beformed and the product mixture is separated using chromatographic orcrystallization techniques to afford the individual isomers.

If the synthesis is conducted with a silyl-substituted acetylene 2b toproduce a silyl-substituted 7-azaindole 3b, then the silyl group is nextconverted to an aryl or substituted aryl group of general formula 3cusing the reactions described later in Scheme E. The 2-arylsubstituted7-azaindole derivatives 3c formed either directly from arylacetylenes(2c) as shown in Scheme A or from 2-trialkylsilyl-7-azaindoles using themethod of Scheme E are then further elaborated as described below toproduce the novel 7-azaindole derivatives described in this invention.##STR8##

Scheme B illustrates the preparation of substituted3-iodo-2-aminopyridines (1) which are utilized in the Larock 7-azaindolesynthesis described in Scheme A. The 3-iodo-2-aminopyridines (1) may beprepared in several ways described in the literature of organicsynthesis. A preferred method involves the ortho-iodination ofsubstituted 2-aminopyridine derivatives of general formula 9 with anelectrophilic iodination reagent such as iodine, iodine monochloride,N-iodosuccinimide or the like. The ortho-iodination of 2-aminopyridinederivatives (9) as illustrated in Scheme B employs iodine and silvertrifluoroacetate in a suitable organic solvent like methanol at roomtemperature and 3-iodo-2-aminopyridines of general formula 1 areproduced in high yield.

In some cases, 2-aminopyridine derivatives such as 9 may be commerciallyavailable or alternatively they may be prepared using methodologiesknown in organic chemistry. For instance, application of methodologyreported by Wachi and Terada (Wachi, K.; Terada, A. Chem. Pharm. Bull.1980, 28, 465) allows the conversion of pyridines of general formula 5to 2-aminopyridines of general formula 9 as shown at the top of SchemeB. In this synthetic transformation, a substituted pyridine (5) is firstconverted to the corresponding N-oxide (6) with a suitable oxidant suchas meta-chloroperbenzoic acid. In the next step, the substitutedpyridine N-oxide 6 is reacted with4-chloro-2,2-dimethyl-2H-1,3-benzoxazine (7) in an inert high boilingsolvent such as 1,2-dichloroethane. An adduct initially formed in thisreaction undergoes a thermal rearrangement and the N-pyridyl substituted4-oxo-4H-1,3-benzoxazine 8 is produced. Finally, the substitutedbenzoxazine 8 is hydrolyzed with concentrated hydrochloric acid atelevated temperature to afford the substituted 2-aminopyridines ofgeneral formula 9. ##STR9##

Acetylenic compounds of general structure 2 are prepared using one ofseveral methods depending upon the choice of the desired substituents.When the substituents R₉, R_(9a), R₁₀ and R_(10a) are selected to behydrogen or lower alkyl groups, compounds of formula 2 may be preparedfrom known acetylenic alcohols such as 3-butyn-1-ol, 4-pentyn-2-ol orsimilar acetylenic alcohols reported in the chemical literature. Theconversion of acetylenic alcohols of general formula 10 to acetylenederivatives of general formula 2 is shown in Scheme C. For clarity thehydroxyl protecting group (PG₁) illustrated in Scheme C is exemplifiedas an O-benzyl ether. Thus, reaction of 10 withO-benzyl-2,2,2-trichloroacetimidate in the presence of a catalyticamount of a strong acid such as trifluoromethanesulfonic acid and in asuitable inert organic solvent like carbon tetrachloride at roomtemperature affords after 2 to 24 hours the protected acetylenic alcohol2a. Compounds of formula 2a may in turn be converted to acetylenes (2b)of general formula 2 wherein Z is a trialkylsilyl group by deprotonationof the acetylene with a base such as n-butyllithium in an inert organicsolvent like tetrahydrofuran followed by reaction with a trialkylsilylchloride such as triethylchlorosilane. The deprotonation and silylationreactions are generally conducted at low temperatures, for instancebetween about -78° C. and room temperature, and after standard workupand purification a silylacetylene of formula 2b is obtained.

As previously stated, acetylenes of general formula 2c wherein Z is anaryl or substituted aryl group, are also useful in the 7-azaindolesynthesis illustrated in Scheme A. Arylacetylenes 2c may be preparedusing a coupling reaction of cuprous acetylides derived from acetylenicalcohols of formula 2a with various aryl halides or aryl triflates (11).Such coupling reactions produce aryl acetylenes of general formula 12 asshown at the bottom of Scheme C. These reactions are generally carriedout in a basic organic solvent like triethylamine at elevatedtemperatures, typically between about 60° C. and about 120° C., and thecoupling reaction is catalyzed by copper(I) salts such as cuprous iodideand a palladium catalyst such as palladium acetate in combination withtriphenylphosphine. The hydroxyl group of the arylacetylenes of generalformula 12 can be protected with a suitable protecting group such as theO-benzyl ether group shown in Scheme C, to afford an arylacetylene (2c)of general formula 2 wherein Z is an aryl or substituted aryl group. Itis also recognized that in some cases it may be preferable to reversethe order of the steps illustrated in Scheme C. For instance, acetylenicalcohols (7) may be subjected to silylation or arylation prior to thehydroxyl group protection step. ##STR10##

Another useful approach for the preparation of acetylenic compounds ofgeneral formula 2a employs an ethynylation reaction sequence ofaldehydes of general formula 16 as shown in Scheme D. The aldehydes (16)used in the ethynylation sequence may be prepared using various methodsknown in organic synthesis starting with hydroxyesters of generalformula 13, from protected hydroxyesters of formula 14, or from alcoholsrelated to the mono-hydroxyl protected diols of formula 15. The choiceof preferred starting material depends upon the nature of thesubstituents R₉, R_(9a), R₁₀, and R_(10a) selected. Scheme D illustratesthis strategy begining with the generalized hydroxy ester 13. Protectionof the hydroxyl group of 13, for instance as the O-benzylether shown,affords a protected hydroxy ester of formula 14. The ester group ofcompounds of formula 14 can then be converted to an aldehyde of formula16 either directly using a reagent like diisobutylaluminum hydride in asolvent like toluene, or through a two step process. In the two stepprocess, reduction of the ester group with a reagent such as lithiumaluminum hydride in tetrahydrofuran affords alcohols of formula 15 whichare then subjected to reoxidation, for instance using a Swern-Moffattoxidation, to afford the desired aldehydes of formula 16.

The ethynylation of aldehydes of formula 16 is accomplished in twosteps. First, aldehydes (16) are reacted with carbon tetrabromide andtriphenylphosphine in an inert organic solvent like dichloromethane toproduce the dibromo olefins of formula 17. Next, the dibromo olefins(17) are treated with two equivalents of a strong base such asn-butyllithium in tetrahydrofuran at low temperature, for instance atabout -78° C. The strong base induces dehydrohalogenation andmetal-halogen exchange to afford lithium acetylides which upon quenchingand workup afford acetylenes of general formula 2a. Alternatively, theintermediate lithium acetylides formed in the reaction may be treatedwith a trialkylsilyl chloride, such as triethylchlorosilane, to affordsilylacetylenes of general formula 2b. ##STR11##

The conversion of 2-silyl-substituted 7-azaindoles of general formula 3bto 2-aryl-substituted 7-azaindoles of general formula 3c may beaccomplished in two steps as shown in Scheme E. The first step is ahalodesilylation reaction which converts silyl-substituted 7-azaindolesof formula 3b into 2-halo-7-azaindoles of general formula 18. Scheme Eillustrates this process using iodine monochloride so that the productobtained is a 2-iodoindole of general formula 18. Silvertetrafluoroborate is also employed in this example to increase thereactivity of the halogenating reagent. It is possible to effect thehalodesilylation reaction with other electrophilic halogenating reagentssuch as N-bromosuccinimide in dichloromethane which affords a2-bromo-7-azaindole derivative. Both 2-bromo and 2-iodo-7-azaindoles offormula 18 are useful in the subsequent step.

The second step is a palladium-catalyzed cross coupling reaction of the2-halo-7-azaindole 18 with a suitable aryl or substituted arylorganometallic reagent 19. Scheme E illustrates this process with anaryl or substituted arylboronic acid as the organometallic reagent,however, other organometallic reagents known to participate inpalladium-catalyzed cross-coupling reactions such as arylboronic estersor arylstannanes may also be employed. In the example, a2-iodo-7-azaindole of general formula 18 is coupled with a generalizedboronic acid (19) using a catalyst such as[1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complexwith dichloromethane (shown), tetrakis(triphenylphosphine)-palladium(O)or the like. The reaction is usually conducted at temperatures betweenroom temperature and about 100° C., for instance at about 80° C. Thispalladium catalyzed cross-coupling reaction may be effected usingvarious combinations of palladium catalysts and solvent compositionsknown in organic chemistry, and the selection of the conditions is madedepending upon the type of organometallic reagent (19) used and theidentity of the substituent groups in the two starting materials. Whenthe organometallic reagent is a boronic acid or boronate ester then apreferred solvent mixture consists of toluene, ethanol and an aqueoussolution of a base like cesium or sodium carbonate. If instead theorganometallic reagent 19 is an arylstannane, then no additional base isrequired, and a polar aprotic solvent such as tetrahydrofuran ordimethylformamide is employed. ##STR12##

The next stage of the synthesis of the novel 7-azaindole derivatives isillustrated in Scheme F. This sequence of reactions begins withprotection of the 7-azaindole with an amine protecting group (PG₂) toafford compounds of general formula 20. The protection step is requiredto avoid competing side rections of the 2-aryltryptophol of formula 21(where PG₂ is H) in the later conversion of compounds of formula 21 tocompounds of formula 22. The indole protection is followed by removal ofthe hydroxyl protecting group (PG₁) from the side chain at the C-3position of the 7-azaindole ring to afford compounds of general formula21. Finally, the hydroxyl group of 21 is converted to a primary amine ofgeneral formula 23 which is then further functionalized as shown belowin the following schemes. The choice of an appropriate amine protectinggroup (PG₂) for the 7-azaindole is determined primarily by whichprotecting group (PG₁) is present on the hydroxyl group in the C-3sidechain, and by consideration of the chemical stability of the amineprotecting group (PG₁) required in the remaining steps of the synthesis.When the hydroxyl protecting group (PG₁) is an O-benzyl ether asillustrated previously in Schemes C and D, the 7-azaindole may beprotected as a carbamate derivative such as a tert-butylcarbamate (BOC).In this case, the BOC-protected 7-azaindole is stable under thehydrogenolysis conditions which are used to remove the O-benzyl etherand it may be conveniently removed at the end of the synthesis usingacidic conditions. If it is desired to synthesize compounds of formula(I) wherein R₀ is alkyl, substituted alkyl or the like, then it ispossible to introduce that substituent at this point and the use of aprotecting group and its subsequent removal is not required.

An alcohol of general formula 21 may be converted to a primary amine ofgeneral formula 23 using a variety of methods known in the literature oforganic chemistry. The bottom of Scheme F illustrates a process wherethe alcohol 21 is first converted to an azide of general formula 22,followed by reduction to afford the amine derivative 23. The synthesisof an azide of general formula 22 from alcohols like 21 is bestaccomplished by performing a Mitsunobu reaction in the presence of anappropriate azide source such as diphenylphosphoryl azide or zinc azidepyridine complex. Scheme F illustrates the reaction of alcohol 21 withtriphenylphosphine, diethylazodicarboxylate, zinc azide pyridine complexand a proton source such as imidazole in an inert solvent like methylenechloride or tetrahydrofuran. The reaction is usually conducted at roomtemperature for periods between 1-24 hours, typically overnight or about15 hours, and affords the azide of general formula 22 in good yield.Finally, an azide of formula 22 may then be reduced to an amine offormula 23 using one of several methods common in organic synthesis. Onepreferred method is catalytic hydrogenation in a solvent like methanolor ethanol in the presence of a catalyst such as 10% palladium oncarbon. Alternatively, azides like 22 may be reacted withtriphenylphosphine to form an iminophosphorane which upon hydrolysiswith water affords the amine of formula 23 and triphenylphophine oxide.##STR13##

The final stage of the synthesis of the novel 7-azaindole derivatives(I) involves elaboration of the sidechain at the C-3 position of the7-azaindole core. One method for the completion of the synthesis isillustrated in Scheme G. As shown, the 2-aryltryptamine (23) may becondensed with a carboxylic acid of type 24 using the coupling reagent1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (EDC),1,3-dicyclohexyl-carbodiimide (DCC) or the like with or without1-hydroxybenzotriazole (HOBt) and a tertiary amine base such asN-methylmorpholine (NMM), triethylamine or the like in an inert organicsolvent such as methylene chloride, chloroform, dimethylformamide, ormixtures thereof at or near room temperature for a period of 3-24 hoursto provide the corresponding amide derivative (25). Alternatively,2-aryltryptamine 23 can be treated with an active ester or acid chlorideof formula 26 in an inert organic solvent such as methylene chloride,chloroform, tetrahydrofuran, diethyl ether, or the like and a tertiaryamine base such as triethylamine, diisopropylethylamine, pyridine or thelike at a temperature of 0°-25° C. for 30 minutes to 4 hours to givecompound 25. ##STR14##

As shown in reaction Scheme H, the amide carbonyl of 25 can be reducedby treatment with borane, lithium aluminum hydride, or equivalenthydride sources in an inert organic solvent such as tetrahydrofuran,diethyl ether, 1,4-dioxane or the like at about 25° to about 100° C.,preferably about 65° C., for a period of 1-8 hours to give thecorresponding amine 27. ##STR15##

As shown in reaction Scheme I, the 2-aryltryptamine 23 can be modifiedby treatment with an aldehyde or ketone of type 28 in the presence of aweak acid such as trifluoroacetic acid (TFA), acetic acid or the like,with or without a dessicant such as 3 Å molecular sieves or magnesiumsulfate, and a hydride source such as sodium borohydride or sodiumcyanoborohydride, in an inert organic solvent such as methanol, ethanol,isopropanol, tetrahydrofuran, dichloromethane, chloroform, or mixturesthereof at a temperature of about 0° to about 25° C. for a period of1-12 hours to give the corresponding secondary or tertiary aminederivative 29. ##STR16##

As shown in reaction Scheme J, the tryptamine 23 can be modified usingthe Fukuyama modification of the Mitsunobu reaction (Fukuyama, T.; Jow,C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373-74). The tryptamine23 may be reacted with an arylsufonyl chloride such as2-nitrobenzene-sulfonyl chloride, 4-nitrobenzenesulfonyl chloride or2,4-dinitrobenzene-sulfonyl chloride and a hindered amine base such as2,4,6-collidine, 2,6-lutidine or the like in an inert organic solventsuch as methylene chloride to provide t he corresponding sulfonamide 30.The sulfonamides can be further modified by reaction with an alcohol oftype 31 in the presence of triphenylphosphine and an activating agentsuch as diethylazodicarboxylate (DEAD), diisopropylazodicaboxylate orthe like in an inert organic solvent such as benzene, toluene,tetrahydrofuran or mixtures thereof to give the dialkylsulfonamideadduct. Removal of a dinitrobenzenesulfonyl group is accomplished bytreatment with a nucleophilic amine such as n-propylamine or the like inan inert organic solvent such as methylene chloride to give secondaryamines of type 32. When a mono-nitrobenzenesulfonyl derivative isemployed, the removal of the sulfonamide is accomplished with a morenucleophilic reagent such as thiophenol or mercaptoacetic acid incombination with lithium hydroxide in DMF. ##STR17##

Reaction Scheme K illustrates a method that is complimentary to reactionScheme J for completing the synthesis of the novel compounds of formula(I). Scheme K also employs the Fukuyama modification of the Mitsunobureaction similar to that illustrated in reaction Scheme J. However inthis instance, the alcohol partner employed is a 2-aryltryptophol ofgeneral formula 21 which has been decribed previously in reaction SchemeF. The 2-aryltryptophol (21) is reacted with a substituted sulfonamideof general formula 33, triphenylphosphine and diethylazodicarboxylate ina suitable inert organic solvent such as benzene, tetrahydrofuran,1,4-dioxane or the like. The reaction is generally conducted at roomtemperature for a period of 2 to 24 hours, typically overnight or forabout 12-16 hours. The product is an N,N-disubstituted sulfonamide whichis then separately subjected to reaction with a base such asn-propylamine which removes the sulfonamide substituent and furnishes asecondary amine related to formula 32. The sulfonamides of formula 33employed are readily obtained from a primary amine and either2-nitrobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride or2,4-dinitrobenzenesulfonyl chloride (as shown) in the presence of ahindered amine base such as 2,4,6-collidine, 2,6-lutidine or the like inan inert organic solvent such as methylene chloride. The final stage ofthe synthesis requires removal of the protecting group on the7-azaindole nitrogen atom (PG₂) which produces a compound of generalformula 32 wherein R₀ is a hydrogen atom. It will be recognized byindividuals skilled in the art of organic synthesis that a preferencefor utilizing either the synthetic sequences outlined in reactionSchemes J or K will be determined by the substituents selected to bepresent in the compounds of formula (I).

The compounds of the present invention are useful in the treatment ofvarious sex-hormone related conditions in men and women. This utility ismanifested in their ability to act as antagonists of the neuropeptidehormone GnRH as demonstrated by activity in the following in vitroassays.

GnRH Receptor Binding Assay:

The ligand binding assay is conducted with the human GnRH receptor(hGnRHR) obtained from CHO-K1 cells stably expressing the clonedreceptor. Crude membrane suspensions are prepared from large batches ofhGnRHR-CHO-K1 cells and stored as aliquots at -80° C. The radioactivepeptide ligand [5-(¹²⁵ Iodo-Tyr)-Buserelin] is obtained from WoodsAssays (Portland, Oreg.) and has a radioactive specific activity of 1000Ci/mmol. The membranes and the radioligand are diluted in assay bufferwhich consists of 50 mM Tris-HCl (pH 7.5), 2 mM MgCl₂ and 0.1% bovineserum albumin. The ligand binding assay is performed at 22° C. for 1hour in 96-well polypropylene plates in a final volume of 200 ul. Eachwell in the assay plate contains 0.1 nM ¹²⁵ I-buserelin, 10-15 ug ofhGnRH receptor-membrane protein and the test compound. Test compoundsare examined over a range of concentrations from 0.01 to 10,000 nM. Theincubation is terminated by vacuum filtration onto 96-well Packard GF/CUnifilter plates (pretreated with 0.1% polyethyleneimine) and thenwashed with 2 mL of cold phosphate buffered saline (pH 7.5). TheUnifilter plates are dried prior to addition of scintillation fluid andcounting in a Packard TopCount detector

Phosphoinositide (PI) Turnover Assay

Chinese hamster ovary cell lines expressing the human GnRH receptorfunctionally coupled to phospholipase C were established and seeded at aconcentration of 60,000 cells/mL/well in inositol-free F12 mediumcontaining 10% dialyzed fetal bovine serum, 1% Pen/Strep, 2 mMglutamine, 500 μg/mL G418 and 1 μCi (³ H)inositol in 24-well tray.Forty-eight hours after seeding, cells were washed with 3×1 mL of PBScontaining 10 mM LiCl and treated with various concentrations of GnRHantagonist for 2 hrs at 37° C. before the addition of 0.5 nM GnRH. Afterincubation at 37° C. for an additional 60 min, the medium was removedand the cells were lysed with 1 mL of 0.1 M formic acid. The trays werefreeze-thawed once and the cell extract was applied onto a Dowex AG1-X8column. The column was washed with 2×1 mL H₂ O to remove free (³H)inositol and (³ H)inositol phosphates were eluted with 3×1 mL 2 Mammonium formate in 1M formic acid. The eluate was then counted in ascintillation counter.

The compounds of formula I are useful in a number of areas affected byGnRH. They may be useful in sex-hormone related conditions, sex-hormonedependent cancers, benign prostatic hypertrophy or myoma of the uterus.Sex-hormone dependent cancers which may benefit from the administrationof the compounds of this invention include prostatic cancer, uterinecancer, breast cancer and pituitary gonadotrophe adenomas. Othersex-hormone dependent conditions which may benefit from theadministration of the compounds of this invention include endometriosis,polycystic ovarian disease, uterine fibroids and precocious puberty. Thecompounds may also be used in combination with an angiotensin-convertingenzyme inhibitor such as Enalapril or Captopril, an angiotensinII-receptor antagonist such as Losartan or a renin inhibitor for thetreatment of uterine fibroids.

The compounds of the invention may also be useful for controllingpregnancy, as a contraceptive in both men and women, for in vitrofertilization, in the treatment of premenstrual syndrome, in thetreatment of lupus erythematosis, in the treatment of hirsutism, in thetreatment of irritable bowel syndrome and for the treatment of sleepdisorders such as sleep apnea.

A further use of the compounds of this invention is as an adjunct togrowth hormone therapy in growth hormone deficient children. Thecompounds may be administered with growth hormone or a compound whichincreases the endogenous production or release of growth hormone.Certain compounds have been developed which stimulate the release ofendogenous growth hormone. Peptides which are known to stimulate therelease of endogenous growth hormone include growth hormone releasinghormone, the growth hormone releasing peptides GHRP-6 and GHRP-1(described in U.S. Pat. No. 4,411,890, PCT Patent Pub. No. WO 89/07110,and PCT Patent Pub. No. WO 89/07111) and GHRP-2 (described in PCT PatentPub. No. WO 93/04081), as well as hexarelin (J. Endocrinol Invest.,15(Suppl 4), 45 (1992)). Other compounds which stimulate the release ofendogenous growth hormone are disclosed, for example, in the following:U.S. Pat. No. 3,239,345; U.S. Pat. No. 4,036,979; U.S. Pat. No.4,411,890; U.S. Pat. No. 5,206,235; U.S. Pat. No. 5,283,241; U.S. Pat.No. 5,284,841; U.S. Pat. No. 5,310,737; U.S. Pat. No. 5,317,017; U.S.Pat. No. 5,374,721; U.S. Pat. No. 5,430,144; U.S. Pat. No. 5,434,261;U.S. Pat. No. 5,438,136; EPO Patent Pub. No. 0,144,230; EPO Patent Pub.No. 0,513,974; PCT Patent Pub. No. WO 94/07486; PCT Patent Pub. No. WO94/08583; PCT Patent Pub. No. WO 94/11012; PCT Patent Pub. No. WO94/13696; PCT Patent Pub. No. WO 94/19367; PCT Patent Pub. No. WO95/03289; PCT Patent Pub. No. WO 95/03290; PCT Patent Pub. No. WO95/09633; PCT Patent Pub. No. WO 95/11029; PCT Patent Pub. No. WO95/12598; PCT Patent Pub. No. WO 95/13069; PCT Patent Pub. No. WO95/14666; PCT Patent Pub. No. WO 95/16675; PCT Patent Pub. No. WO95/16692; PCT Patent Pub. No. WO 95/17422; PCT Patent Pub. No. WO95/17423; Science, 260, 1640-1643 (Jun. 11, 1993); Ann. Rep. Med. Chem.,28, 177-186 (1993); Bioorg. Med. Chem. Ltrs., 4(22), 2709-2714 (1994);and Proc. Natl. Acad. Sci. USA 92, 7001-7005 (July 1995).

Representative preferred growth hormone secretagoues employed in thepresent combination include the following:

1)N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(1H-indol-3-yl)ethyl]-2-amino-2-methyl-propanamide;

2)N-[1(R)-[(1,2-Dihydro-1-methanecarbonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(1H-indol-3-yl)ethyl]-2-amino-2-methyl-propanamide;

3)N-[1(R)-[(1,2-Dihydro-1-benzenesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(1H-indol-3-yl)ethyl]-2-amino-2-methyl-propanamide;

4)N-[1(R)-[(3,4-Dihydro-spiro[2H-1-benzopyran-2,4'-piperidin]-1'-yl)carbonyl]-2-(1H-indol-3-yl)ethyl]-2-amino-2-methylpropanamide;

5)N-[1(R)-[(2-Acetyl-1,2,3,4-tetrahydrospiro[isoquinolin-4,4'-piperidin]-1'-yl)carbonyl]-2-(indol-3-yl)ethyl]-2-amino-2-methyl-propanamide;

6)N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide;

7)N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamidemethanesulfonate;

8)N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(2',6'-difluorophenylmethyloxy)ethyl]-2-amino-2-methylpropanamide;

9)N-[1(R)-[(1,2-Dihydro-1-methanesulfonyl-5-fluorospiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide;

10)N-[1(S)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(phenylmethylthio)ethyl]-2-amino-2-methylpropanamide;

11)N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-3-phenylpropyl]-2-amino-2-methylpropanamide;

12)N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-3-cyclohexylpropyl]-2-amino-2-methylpropanamide;

13)N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-4-phenylbutyl]-2-amino-2-methylpropanamide;

14)N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(5-fluoro-1H-indol-3-yl)ethyl]-2-amino-2-methylpropanamide;

15)N-[1(R)-[(1,2-Dihydro-1-methanesulfonyl-5-fluorospiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(5-fluoro-1H-indol-3-yl)ethyl]-2-amino-2-methylpropanamide;

16)N-[1(R)-[(1,2-Dihydro-1-(2-ethoxycarbonyl)methylsulfonylspiro-[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(1H-indol-3-yl)ethyl]-2-amino-2-methylpropanamide;

17)N-[1(R)-[(1,2-Dihydro-1,1-dioxospiro[3H-benzothiophene-3,4'-piperidin]-1'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide;

and pharmaceutically acceptable salts thereof.

The compounds of the invention may also be used in combination withbisphosphonates (bisphosphonic acids) and other agents, such as growthhormone secretagogues, for the treatment and the prevention ofdisturbances of calcium, phosphate and bone metabolism, in particular,for the prevention of bone loss during therapy with the GnRH antagonist,and in combination with estrogens, progesterones and or androgens forthe prevention or treatment of bone loss or hypogonadal symptoms such ashot flashes during therapy with the GnRH antagonist.

Bisphosphonates (bisphosphonic acids) are known to inhibit boneresorption and are useful for the treatment of bone lithiasis asdisclosed in U.S. Pat. No. 4,621,077 to Rosini, et al.

The literature discloses a variety of bisphosphonic acids which areuseful in the treatment and prevention of diseases involving boneresorption. Representative examples may be found in the following: U.S.Pat. No. 3,251,907; U.S. Pat. No. 3,422,137; U.S. Pat. No. 3,584,125;U.S. Pat. No. 3,940,436; U.S. Pat. No. 3,944,599; U.S. Pat. No.3,962,432; U.S. Pat. No. 4,054,598; U.S. Pat. No. 4,267,108; U.S. Pat.No. 4,327,039; U.S. Pat. No. 4,407,761; U.S. Pat. No. 4,578,376; U.S.Pat. No. 4,621,077; U.S. Pat. No. 4,624,947; U.S. Pat. No. 4,746,654;U.S. Pat. No. 4,761,406; U.S. Pat. No. 4,922,007; U.S. Pat. No.4,942,157; U.S. Pat. No. 5,227,506; U.S. Pat. No. 5,270,365; EPO PatentPub. No. 0,252,504; and J. Org. Chem., 36, 3843 (1971).

The preparation of bisphosphonic acids and halo-bisphosphonic acids iswell known in the art. Representative examples may be found in the abovementioned references which disclose the compounds as being useful forthe treatment of disturbances of calcium or phosphate metabolism, inparticular, as inhibitors of bone resorption.

Preferred bisphosphonates are selected from the group of the followingcompounds: alendronic acid, etidrononic acid, clodronic acid, pamidronicacid, tiludronic acid, risedronic acid,6-amino-1-hydroxy-hexylidene-bisphosphonic acid, and1-hydroxy-3(methylpentylamino)-propylidene-bisphosphonic acid; or anypharmaceutically acceptable salt thereof. A particularly preferredbisphosphonate is alendronic acid (alendronate), or a pharmaceuticallyacceptable salt thereof. An especially preferred bisphosphonate isalendronate sodium, including alendronate sodium trihydrate. Alendronatesodium has received regulatory approval for marketing in the UnitedStates under the trademark FOSAMAX®.

Additionally, a compound of the present invention may be co-administeredwith a 5α-reductase 2 inhibitor, such as finasteride or epristeride; a5α-reductase 1 inhibitor such as 4,7β-dimethyl-4-aza-5α-cholestan-3-one,3-oxo-4-aza-4,7β-dimethyl-16β-(4-chlorophenoxy)-5α-androstane, and3-oxo-4-aza-4,7β-dimethyl-16β-(phenoxy)-5α-androstane as disclosed in WO93/23420 and WO 95/11254; dual inhibitors of 5α-reductase 1 and5α-reductase 2 such as3-oxo-4-aza-17β-(2,5-trifluoromethylphenyl-carbamoyl)-5α-androstane asdisclosed in WO 95/07927; antiandrogens such as flutamide, casodex andcyproterone acetate, and alpha-1 blockers such as prazosin, terazosin,doxazosin, tamsulosin, and alfuzosin.

Further, a compound of the present invention may be used in combinationwith growth hormone, growth hormone releasing hormone or growth hormonesecretagogues, to delay puberty in growth hormone deficient children,which will allow them to continue to gain height before fusion of theepiphyses and cessation of growth at puberty.

Further, a compound of the present invention may be used in combinationor co-administered with a compound having luteinizing hormone releasingactivity such as a peptide or natural hormone or analog thereof. Suchpeptide compounds include leuprorelin, gonadorelin, buserelin,triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterlin andrecirelin.

For combination treatment with more than one active agent, where theactive agents are in separate dosage formulations, the active agents maybe administered separately or in conjunction. In addition, theadministration of one element may be prior to, concurrent to, orsubsequent to the administration of the other agent.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example, magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the technique described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethylene-oxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof an oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example soy beans, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

Compounds of Formula I may also be administered in the form of asuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compound of Formula I are employed. (For purposesof this application, topical application shall include mouth washes andgargles.)

The compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal routes, using those forms of transdermal skin patches wellknown to those of ordinary skill in the art. To be administered in theform of a transdermal delivery system, the dosage administration will,of course, be continuous rather than intermittent throughout the dosageregimen. Compounds of the present invention may also be delivered as asuppository employing bases such as cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, mixtures of polyethylene glycols of variousmolecular weights and fatty acid esters of polyethylene glycol.

The dosage regimen utilizing the compounds of the present invention isselected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient; theseverity of the condition to be treated; the route of administration;the renal and hepatic function of the patient; and the particularcompound thereof employed. A physician or veterinarian of ordinary skillcan readily determine and prescribe the effective amount of the drugrequired to prevent, counter, arrest or reverse the progress of thecondition. Optimal precision in achieving concentration of drug withinthe range that yields efficacy without toxicity requires a regimen basedon the kinetics of the drug's availability to target sites. Thisinvolves a consideration of the distribution, equilibrium, andelimination of a drug. Preferably, doses of the compound of structuralformula I useful in the method of the present invention range from 0.01to 1000 mg per adult human per day. Most preferably, dosages range from0.1 to 500 mg/day. For oral administration, the compositions arepreferably provided in the form of tablets containing 0.01 to 1000milligrams of the active ingredient, particularly 0.01, 0.05, 0.1, 0.5,1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of theactive ingredient for the symptomatic adjustment of the dosage to thepatient to be treated. An effective amount of the drug is ordinarilysupplied at a dosage level of from about 0.0002 mg/kg to about 50 mg/kgof body weight per day. The range is more particularly from about 0.001mg/kg to 1 mg/kg of body weight per day.

Advantageously, the active agent of the present invention may beadministered in a single daily dose, or the total daily dosage may beadministered in dividend doses of two, three or four times daily.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

The following examples illustrate the preparation of some of thecompounds of the invention and are not to be construed as limiting theinvention disclosed herein.

EXAMPLE 1(S)-N-[4-(2-{2-[5-[2-(N,N-Diisobutylamino)-1,1-dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]propylamino}ethyl)phenyl]methanesulfonamide##STR18## Step 1A: Methyl(S)-2-[3-(2-benzyloxy-1-methylethyl)-2-triethylsilyl-1-H-pyrrolo[2,3-b]pyridin-5-yl]-2-methylpropanoate

A vigorously stirred suspension of methyl2-(6-amino-5-iodopyridin-3-yl)-2-methylpropanoate (4.61 g, 14.4 mmol),(S)-(4-benzyloxy-3-methylbut-1-ynyl)triethylsilane (4.98 g, 17.3 mmol),Pd(dppf)Cl₂.CH₂ Cl₂ (0.59 g, 0.72 mmol) LiCl (0.61 g, 14.4 mmol), Na₂CO₃ (3.82 g, 36.0 mmol) and N,N-dimethylformamide (60 mL) was degassedvia three vacuum/nitrogen ingress cycles and the resulting mixture washeated at approximately 90° C. overnight. After cooling to ambienttemperature, the reaction mixture was diluted with ethyl acetate andfiltered through celite® washing copiously with ethyl acetate. Thefiltrate was poured into water and extracted with ethyl acetate (×3).The combined organic extract was washed with brine, dried (MgSO₄) andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel (gradient elution; 20-25% ethyl acetate/hexanes as eluent)to give the title compound as a viscous pale yellow oil (6.11 g, 95%).

Step 1B: Methyl(S)-2-[3-(2-benzyloxy-1-methylethyl)-2-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-methylpropanoate

A solution of iodine monochloride (2.83 g, 17.4 mmol) in MeOH (25 mL)was added over approximately 0.5 h via pressure equalizing additionfunnel to a vigorously stirred mixture of methyl(S)-2-[3-(2-benzyloxy-1-methylethyl)-2-triethylsilyl-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-methylpropanoate(6.00 g, 13.4 mmol) and silver tetrafluoroborate (3.39 g, 17.4 mmol) inMeOH/THF (1:2; 75 mL) at 0° C. After an additional 0.5 h, the reactionwas quenched with 1M Na₂ S₂ O₃, warmed to room temperature and filteredthrough celite® washing copiously with ethyl acetate. The filtrate wasconcentrated under reduced pressure, poured into 1M Na₂ S₂ O₃ andextracted with ethyl acetate (¥3). The combined organic extract waswashed with brine, dried (MgSO₄) and concentrated in vacuo. The residuewas purified by flash chromatography on silica gel (25% ethylacetate/hexanes as eluent) to give the title compound as a colourlesssolid (5.54 g, 84%).

Step 1C: Methyl(S)-2-[3-(2-benzyloxy-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-methylpropanoate

A vigorously stirred suspension of methyl(S)-2-[3-(2-benzyloxy-1-methylethyl)-2-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-methylpropanoate(4.00 g, 8.12 mmol), 2,5-dimethylphenylboronic acid (1.83 g, 12.2 mmol)and Pd(dppf)Cl₂.CH₂ Cl₂ (0.33 g, 0.406 mmol) in toluene/MeOH (5:2; 140mL) was degassed via three vacuum/nitrogen ingress cycles and theresulting mixture was heated to approximately 80° C. 1M Na₂ CO₃ (20.3mL, 20.3 mmol) was added dropwise via syringe and the resulting mixturemaintained at reflux overnight. After cooling to ambient temperature,the reaction mixture was diluted with ethyl acetate and filtered throughcelite® washing copiously with ethyl acetate. The filtrate was pouredinto water and extracted with ethyl acetate (×3). The combined organicextract was washed with brine, dried (MgSO₄) and concentrated in vacuo.The residue was purified by flash chromatography on silica gel (25%ethyl acetate/hexanes as eluent) to afford the title compound as acolourless foam (3.82 g, 100%).

Step 1D:(S)-2-[3-(2-Benzyloxy-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-methylpropanoicacid

A vigorously stirred suspension of methyl(S)-2-[3-(2-benzyloxy-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-methylpropanoate(3.82 g, 8.12 mmol) and 2N KOH (40.6 mL, 0.081 mol) in MeOH (40 mL) washeated at 80° C. for approximately 4 h. After cooling to roomtemperature, the reaction mixture was acidified to pH 6 with 2N HCl andextracted with ethyl acetate (×3). The combined organic extract waswashed with brine, dried (MgSO₄) and concentrated in vacuo. The cruderesidue was used without further purification in the subsequentreaction.

Step 1E:(S)-1-(N,N-Diisobutylamino)-2-[3-(2-benzyloxy-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-pyrrolo[2,3-b]-pyridin-5-yl]-2-methylpropan-1-one

PyBOP is added to a stirred mixture of(S)-2-[3-(2-benzyloxy-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-pyrrolo-[2,3-b]pyridin-5-yl]-2-methylpropanoicacid, diisobutylamine and triethylamine in CH₂ Cl₂ at ambienttemperature. After approximately 12 h, the reaction mixture is pouredinto waterlbrine (1:1) and extracted with ethyl acetate. The combinedorganic extract is washed with brine, dried (MgSO₄) and concentrated invacuo. The residue is purified by flash chromatography on silica gel(gradient elution; 60-75% ethyl acetate/hexanes as eluent) to give thetitle compound.

Step 1F:(S)-1-(N,N-Diisobutylamino)-2-[3-(2-benzyloxy-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-1-(tert-butoxycarbonyl)pyrrolo[2,3-b]pyridin-5-yl]-2-methylpropan-1-one

Di-tert-butyldicarbonate is added to stirred suspension of(S)-1-(N,N-diisobutylamino)-2-[3-(2-benzyloxy-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-methylpropan-1-one,DMAP, and potassium carbonate in CH₂ Cl₂ at room temperature. Afterapproximately 3 h, the reaction mixture is poured into water andextracted with ethyl acetate. The combined organic extract is washedwith brine, dried (MgSO₄) and concentrated in vacuo. The residue ispurified by flash chromatography on silica gel (60% ethylacetate/hexanes as eluent) to give the title compound.

Step 1G:(S)-1-(N,N-Diisobutylamino)-2-[3-(2-hydroxy-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-1-(tert-butoxycarbonyl)pyrrolo[2,3-b]pyridin-5-yl]-2-methylpropan-1-one

A mixture of(S)-1-(N,N-diisobutylamino)-2-[3-(2-benzyloxy-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-1-(tert-butoxycarbonyl)pyrrolo[2,3-b]pyridin-5-yl]-2-methylpropan-1-oneand Pd(OH)₂ (Pd-20%) in glacial acetic acid/EtOH (1:1) is hydrogenatedat 50 psi for about 4 days. The resulting mixture is filtered throughcelite® washing copiously with EtOH, the filtrate is evaporated in vacuoand the residue purified by flash chromatography on silica gel (gradientelution; 75-90% ethyl acetate/hexanes) to give the title compound.

Step 1H:(S)-1-(N,N-Diisobutylamino)-2-[3-(2-azido-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-1-(tert-butoxycarbonyl)pyrrolo[2,3-b]pyridin-5-yl]-2-methylpropan-1-one

DEAD is added dropwise via syringe to a stirred solution of(S)-1-(N,N-diisobutylamino)-2-[3-(2-hydroxy-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-1-(tert-butoxycarbonyl)pyrrolo[2,3-b]pyridin-5-yl]-2-methylpropan-1-one,ZnN₆.2py, PPh₃ and imidazole in CH₂ Cl₂ at approximately 0° C. Thereaction mixture is allowed to warm to room temperature overnight, thenfiltered through celite® washing copiously with CH₂ Cl₂. The filtrate ispoured into water and extracted with CH₂ Cl₂, and the combined organicextract is washed with brine, dried (MgSO₄) and concentrated in vacuo.The residue is purified by flash chromatography on silica gel (gradientelution; 25-40% ethyl acetate/hexanes as eluent) to give the titlecompound.

Step 1I:(S)-1-(N,N-Diisobutylamino)-2-[3-(2-amino-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-1-(tert-butoxycarbonyl)pyrrolo[2,3-b]pyridin-5-yl]-2-methylpropan-1-one

A mixture of(S)-1-(N,N-diisobutylamino)-2-[3-(2-azido-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-1-(tert-butoxycarbonyl)pyrrolo[2,3-b]pyridin-5-yl]-2-methylpropan-1-oneand Pd/C (Pd-10%) in MeOH/EtOH is hydrogenated at 50 psi overnight. Theresulting mixture is filtered through celite® washing copiously withEtOH, the filtrate is evaporated in vacuo and the residue purified bypreparative thin layer chromatography on silica gel (100% ethyl acetateas eluent) to give the title compound.

Step 1J:(S)-1-(N,N-Diisobutylamino)-2-[3-(2-(2,4-dinitrobenzenesulfonylamino)-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-1-(tert-butoxycarbonyl)pyrrolo[2,3-b]pyridin-5-yl]-2-methylpropan-1-one

2,4-Dinitrobenzenesulfonyl chloride is added to a stirred solution of(S)-1-(N,N-diisobutylamino)-2-[3-(2-amino-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-1-(tert-butoxycarbonyl)pyrrolo[2,3-b]pyridin-5-yl]-2-methylpropan-1-oneand 2,4,6-collidine in CH₂ Cl₂ at approximately 0° C. After 5 min, theresulting mixture is warmed to ambient temperature and aged for 2 h. Thereaction mixture is poured into water and extracted with ethyl acetate.The combined organic extract is washed with brine, dried (MgSO₄) andconcentrated in vacuo. The residue is purified by flash chromatographyon silica gel (gradient eluton; 60-75% ethyl acetate/hexanes as eluent)to give the title compound.

Step 1K:(S)-N-{4-(2-[N-(5-[2-(N,N-Diisobutylamino)-1,1-dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-1-(tert-butoxycarbonyl)pyrrolo[2,3-b]pyridin-3-yl]propyl)-N-(2,4-dinitrobenzenesulfonyl)]aminoethyl)phenyl}methanesulfonimide

DEAD is added dropwise via syringe to a stirred solution of(S)-1-(N,N-diisobutylamino)-2-[3-(2-(2,4-dinitrobenzenesulfonylamino)-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-1-(tert-butoxycarbonyl)pyrrolo[2,3-b]pyridin-5-yl]-2-methylpropan-1-one,N-[4-(2-hydroxyethyl)phenyl]methanesulfonimide and PPh₃ in benzene atroom temperature. After approximately 2 h, the reaction mixture isconcentrated in vacuo and the residue is purified by flashchromatography on silica gel (60% ethyl acetate/hexanes as eluent) togive the title compound.

Step 1L:(S)-N-[4-(2-{2-[5-[2-(N,N-Diisobutylamino)-1,1-dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-1-(tert-butoxycarbonyl)pyrrolo[2,3-b]pyridin-3-yl]propylamino}ethyl)phenyl]methanesulfonimide

n-Propylamine is added to a stirred solution of(S)-N-{4-(2-[N-(5-[2-(N,N-diisobutylamino)-1,1-dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]propyl)-N-(2,4-dinitrobenzenesulfonyl)]aminoethyl)phenyl}methanesulfonimidein CH₂ Cl₂ at room temperature. After approximately 20 min., thevolatiles are evaporated in vacuo and the residue is purified bypreparative thin layer chromatography on silica gel (100% ethyl acetateas eluent) to give the title compound.

Step 1M:(S)-N-[4-(2-{2-[5-[2-(N,N-Diisobutylamino)-1,1-dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-propylamino}ethyl)phenyl]methanesulfonimide

A solution of(S)-N-[4-(2-{2-[5-[2-(N,N-diisobutylamino)-1,1-dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-1-(tert-butoxycarbonyl)pyrrolo[2,3-b]pyridin-3-yl]propylamino}ethyl)phenyl]methanesulfonimidein trifluoroacetic acid/CH₂ Cl₂ is aged for approximately 3 h. Theresulting mixture is concentrated in vacuo and the residue partitionedbetween saturated aqueous NaHCO₃ and CH₂ Cl₂. The organic phase isseparated and the aqueous phase re-extracted with CH₂ Cl₂. The combinedorganic extract is washed with brine, dried (MgSO₄), and concentrated invacuo. The residue containing the title compound is used directly in thenext step without further purification.

Step 1N:(S)-N-[4-(2-{2-[5-[2-(N,N-Diisobutylamino)-1,1-dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]propylamino}ethyl)phenyl]methanesulfonamide

A solution of 10N KOH is added to a stirred solution of(S)-N-[4-(2-{2-[5-[2-(N,N-diisobutylamino)-1,1-dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]propylamino}ethyl)phenyl]methanesulfonimidein MeOH at room temperature. The resulting mixture is warmed toapproximately 35° C. and aged for 1.5 h. After cooling to roomtemperature, the reaction mixture is poured into saturated aqueousNaHCO₃ and extracted with ethyl acetate. The combined organic extract iswashed with brine, dried (MgSO₄) and concentrated in vacuo. The residueis purified by preparative thin layer chromatography on silica gel (5%MeOH/ethyl acetate as eluent) to give the title compound.

PREPARATION OF SYNTHETIC INTERMEDIATES Methyl2-(6-amino-5-iodopyridin-3-yl)-2-methylpropanoate

Step A: Ethyl 2-methyl-2-(pyridin-3-yl)propanoate

A solution of ethyl-3-pyridylacetate (10.0 g, 60.5 mmol) in THF (50 mL)was added over approximately 0.5 h via pressure equalizing additionfunnel to a stirred mixture of potassium hexamethyldisilazane (48.3 g,0.242 mmol) in THF (250 mL) at -20° C. After 0.5 h, MeI was addeddropwise so as to maintain the internal temperature between -15° C. to-20° C. After warming to approximately 0° C. over 12 h, the reaction wasquenched with saturated aqueous NH₄ Cl and concentrated under reducedpressure. The residue was partitioned between ethyl acetate and water,the organic phase separated and the aqueous phase re-extracted withethyl acetate (×3). The combined organic extract was washed with brine,dried (MgSO₄) and concentrated in vacuo. The residue was purified byflash chromatography on silica gel (30% ethyl acetate/hexanes as eluent)to give the title compound as a pale yellow oil (10.1 g, 86%).

Step B: Ethyl 2-methyl-2-(pyridin-3-yl)propanoate-N-oxide

Meta-chloroperoxybenzoic acid (55%; 21.3 g, 67,9 mmol) was added in oneportion to a vigorously stirred emulsion of ethyl2-methyl-2-(pyridin-3-yl)propanoate and NaHCO₃ (17.5 g, 0.209 mmol) inwater/chloroform (1:1; 500 mL) at ambient temperature. Afterapproximately 12 h, the organic phase was separated and the aqueousphase extracted with chloroform (×3). The combined organic extract waswashed with brine, dried (MgSO₄) and concentrated in vacuo. The residue(10.9 g, 100%) was judged pure by a combination of TLC and ¹ H nmranalysis and was used without further purification in the subsequentreaction.

Step C: Ethyl2-[6-(2,2-dimethyl-4-oxo-4H-1,3-benzoxazin-3-yl)-pyridin-3-yl]-2-methylpropanoate

A solution of 4-chloro-2,2-dimethyl-2H-1,3-benzoxazine (10.1 g, 51.6mmol) and ethyl 2-methyl-2-(pyridin-3-yl)propanoate-N-oxide (9.0 g, 43.0mmol) in 1,2-dichloroethane (100 mL) was heated at approximately 90° C.for 3 d. After cooling to room temperature, the solvent was evaporatedunder reduced pressure and the residue purified by flash chromatographyon silica gel (gradient elution; 20-25% ethyl acetate/hexanes as eluent)to give the title compound as a pale yellow viscous oil (14.3 g, 90%).

Step D: 2-(6-Aminopyridin-3-yl)-2-methylpropanoic acid hydrochloride

A stirred mixture of ethyl2-[6-(2,2-dimethyl-4-oxo-4H-1,3-benzoxazin-3-yl)-pyridin-3-yl]-2-methylpropanoate(13.3 g, 36.1 mmol) in concentrated HCl (50 mL) was heated at 100° C.overnight. After cooling to ambient temperature, the reaction mixturewas concentrated in vacuo and the residue washed exhaustively withchloroform to give the title compound as a colourless solid (6.90 g,88%).

Step E: Methyl 2-(6-aminopyridin-3-yl)-2-methylpropanoate

A solution of 2-(6-aminopyridin-3-yl)-2-methylpropanoic acidhydrochloride (35.0 g, 0.162 mmol) and concentrated H₂ SO₄ (5 mL) inMeOH (250 mL) was heated at reflux overnight. After cooling to ambienttemperature, the reaction was quenched cautiously with saturated aqueousNaHCO₃ and concentrated in vacuo. The residue was partitioned betweenethyl acetate and water, the organic phase separated and the aqueousphase re-extracted with ethyl acetate (×3). The combined organic extractwas washed with brine, dried (MgSO₄) and concentrated in vacuo. Theresidue (31.6 g, 100%) was judged pure by a combination of TLC and ¹ Hnmr analysis and was used without further purification in the subsequentreaction.

Step F: Methyl 2-(6-amino-5-iodopyridin-3-yl)-2-methylpropanoate

A solution of methyl 2-(6-aminopyridin-3-yl)-2-methylpropanoate (10.0 g,51.5 mmol) in MeOH (50 mL) was added over approximately 0.5 h viapressure equalizing addition funnel to a vigorously stirred suspensionof iodine (17.0 g, 67.0 mmol) and silver trifluoroacetate (14.8 g, 67.0mmol) in MeOH (200 mL) at room temperature. After 3 h, the reaction wasquenched sequentially with 1M Na₂ S₂ O₃ followed by saturated aqueousNaHCO₃. The resulting mixture was filtered through celite® washingcopiously with ethyl acetate, the filtrate concentrated in vacuo and theresidue partitioned between ethyl acetate and water. The organic phasewas separated and the aqueous phase was re-extracted with ethyl acetate(×3). The combined organic extract was washed with brine, dried (MgSO₄)and concentrated in vacuo. The residue was purified by flashchromatography on silica gel (gradient elution; 35-40% ethylacetate/hexanes as eluent) to give the title compound as an off-whitesolid (10.3 g, 62%).

(S)-(4-Benzyloxy-3-methylbut-1-ynyl)triethylsilane

Step AA: Methyl (S)-3-benzyloxy-2-methylpropanoate

An oven dried 1 L single-necked round bottom flask was equipped with amagnetic stir bar and then charged sequentially with 15.948 g (0.135mol) of (R)-(-)-methyl-3-hydroxy-2-methylpropanoate, carbontetrachloride (150 mL), cyclohexane (300 mL), and 35.796 g (0.142 mol)of benzyl 2,2,2-trichloroacetimidate. Trifluoromethanesulfonic acid (0.8mL; 9.0 mmol) was added to the solution and the resulting mixture wasstirred for 16 h at room temperature under an N₂ atmosphere. Thereaction mixture was then filtered and the filtrate concentrated invacuo. The residue was redissolved in 150 mL EtOAc and extracted withsaturated aqueous NaHCO₃ (1×100 mL). The organic layer was washed withsaturated NaCl, dried (MgSO₄), filtered and evaporated. The residual oilwas purified on a silica gel flash chromatography column eluted with 10%EtOAc-hexane. The purified fractions were combined and evaporated invacuo to afford 20.787 (74%) of the title compound as a colorless oil.

MS (CI): m/e=209 (M+1).

Step BB: (S)-3-Benzyloxy-2-methylpropan-1-ol

An oven dried three-necked 2 L round bottom flask was equipped with amechanical stirrer, a reflux condenser and a 500 mL constant pressureaddition funnel. The flask was charged with a solution of 62.252 g(0.299 mol) of methyl (S)-3-benzyloxy-2-methylpropanoate in 600 mL ofanhydrous THF, and a 1.0 M solution of lithium aluminum hydride (300 mL;0.3 mol) was transferred into the dropping funnel via a cannula.Stirring was started and the lithium aluminum hydride solution was addedover 45 minutes to the reaction under an N₂ atmosphere while thetemperature of the reaction mixture was maintained between 25-30° C.using an external ice-water bath. After the addition was complete, thereaction was stirred an additional 6 h at room temperature at whichpoint TLC analysis (20% EtOAc-hexane) indicated complete reaction. Thereaction mixture was then cooled with an external ice-water bath andquenched by serial addition of 11.4 mL water, 11.4 mL of 15% aqueousNaOH, and 34.2 mL water. The reaction mixture was then filtered, thesolids were washed with EtOAc, the filtrate and washings were combinedand evaporated in vacuo. The residue was redissolved in EtOAc, washedwith 10% aqueous NaHSO₄, saturated NaCl, dried (MgSO₄), filtered andevaporated. The residue was purified by Kugelrohr distillation to afford47.67 g (89%) of the title compound as a colorless oil.

MS (CI): m/e =181 (M+1).

Step CC: (S)-3-Benzyloxy-2-methylpropanal

An oven dried three-necked 2 L round bottom flask was equipped with amechanical stirrer, a thermometer, an N₂ inlet, and a septum. The flaskwas charged with 24.050 g (0.189 mol) of oxalyl chloride and 425 mL CH₂Cl₂. The reaction mixture was stirred under an N₂ atmosphere and cooledto -78° C. with an external dry ice-acetone bath. A solution of methylsulfoxide (29.607 g; 0.379 mol) in 85 mL CH₂ Cl₂ was then added over 5min to the reaction mixture via cannula. After the adition, the reactionwas stirred an additional 5 min and then a solution of 31.048 g (0.172mol) of (S)-3-benzyloxy-2-methylpropan-1-ol in 170 mL CH₂ Cl₂ was addedvia cannula. When the second addition was completed the reaction mixturewas stirred for 15 min at -78° C. then 111.32 g (0.861 mol) ofN,N-diisopropylethylamine was added via syringe. The reaction mixturewas stirred an addition 15 min at -78° C., the cooling bath was removedand the reaction was allowed to warm. When the internal temperature hadreached -15° C., 350 mL of a 10% aqueous NaHSO₄ solution was slowlyadded and the mixture was transferred to a separatory funnel. Theorganic layer was separated, washed with aqueous NaHSO₄ (2×250 mL),saturated NaCl, dried (MgSO₄), filtered and evaporated. The residue wasused immediately in the next step without further purification.

Step DD: (S)-4-Benzyloxy-1,1-dibromo-3-methylbutene

An oven dried three-necked 2 L round bottom flask was equipped with amechanical stirrer, a thermometer, an N₂ inlet, and a septum. The flaskwas charged with 180.71 g (0.689 mol) of triphenylphosphine and 925 mLof CH₂ Cl₂. The reaction mixture was stirred under an N₂ atmosphere andcooled to 0-5° C. with an external ice-water bath. The septum was thenremoved and 114.25 g (0.344 mol) of carbon tetrabromide was added inportions through the open neck of the flask at a rate that maintainedthe temperature of the reaction mixture below 20° C. After the additionwas complete the reaction was stirred for 1 h and then a solution of the(S)-3-benzyloxy-2-methylpropanal from the previous step dissolved in 150mL of CH₂ Cl₂ was added via cannula over a 5 min period. The reactionmixture was stirred under N₂ for an additional 1 h and allowed to warmto room temperature. A separate 10 L three-necked round bottom flask wasequipped with a mechanical stirrer and charged with 4 L of hexane. Thestirrer was started and the crude reaction mixture was introduced as aslow stream which resulted in formation of a granular precipitate. Afterthe transfer was complete the reaction mixture was filtered and thesolids were carefully washed with hexane. The filtrate was evaporated invacuo and additional solids were deposited. The residue was resuspendedin hexane, filtered and the filtrate reevaporated. The resulting oil waspurified by Kugelrohr distillation to afford 46.54 g (81% for two steps)of the title compound as a colorless oil.

Step EE: (S)-(4-benzyloxy-3-methylbut-1-ynyl)triethylsilane

An oven dried 100 mL single-necked round bottom flask was equipped witha magnetic stir bar and a septum then charged with 5.171 g (15.5 mmol)of (S)-4-benzyloxy-1,1-dibromo-3-methylbutene and 20 mL of anhydrousTHF. The reaction mixture was stirred at -78° C. under an N₂ atmosphereand 12.4 mL of a 2.5 M solution of n-butyllithium (31.0 mmol) was addeddropwise via syringe over 15 min. The reaction mixture was stirred at-78° C. for an additional 1 h, then quenched with 10% aqueous NaHSO₄ andextracted into EtOAc. The organic layer was washed with water (3×25 mL),saturated NaCl, then dried (MgSO₄), filtered, and evaporated. Theresidue was purified by Kugelrohr distillation to afford 3.999 g (90%)of the title compound as a colorless oil.

N-[4-(2-Hydroxyethyl)phenyl]methanesulfonimide

Step AAA: 4-[2-(tert-Butyldimethylsilyloxy)ethyl]aniline

Tert-Butyldimethylsilyl chloride (1.32 g, 8.75 mmol.) was added in oneportion to a stirred solution of 2-(4-aminophenyl)ethanol (1.00 g, 7.29mmol.), DMAP (89.1 mg, 0.729 mmol.) and triethylamine (2.4 mL, 17.5mmol.) in CH₂ Cl₂ (36 mL) at room temperature. After approximately 1 h,the reaction mixture was poured into water and extracted with CH₂ Cl₂(×3). The combined organic extract was washed with brine, dried (MgSO₄)and concentrated in vacuo. The residue was purified by flashchromatography on silica gel (20% ethyl acetate/hexanes as eluent) togive the title compound as a colourless oil (1.65 g, 90% overall).

Step BBB:N-[4-(2-(tert-Butyldimethylsilyloxy)ethyl)phenyl]methanesulfonimide

Methanesulfonyl chloride (0.77 mL, 9.95 mmol.) was added dropwise viasyringe to a stirred solution of4-[2-(tert-butyldimethylsilyloxy)ethyl]aniline (1.00 g, 3.98 mmol.) andtriethylamine (2.77 mL, 19.9 mmol.) in CH₂ Cl₂ (20 mL) at approximately0° C. After 1 h, the reaction mixture was warmed to room temperature andaged for 6 h. The resulting mixture was poured into water and extractedwith ethyl acetate (×3). The combined organic extract was washed withbrine, dried (MgSO₄) and concentrated in vacuo to afford crude the titlecompound as a yellow solid

Step CCC: N-[4-(2-Hydroxyethyl)phenyl]methanesulfonimide

Trifluoroacetic acid (5 mL) was added to a stirred solution of crudeN-[4-(2-(tert-butyldimethylsilyloxy)ethyl)phenyl]methanesulfonimide(3.98 mmol) in CH₂ Cl₂ (20 mL) at room temperature. After approximately0.5 h, the volatiles were evaporated in vacuo and the residue waspurified by flash chromatography on silica gel (gradient elution; 50-60ethyl acetate/hexanes as eluent) to give the title compound as acolorless solid (1.00 g, 86%).

Following procedures similar to those described above, the followingcompounds are prepared: ##STR19##

    ______________________________________                                        Ex. #                                                                         (A)-R.sub.1                                                                   ______________________________________                                        1A                                                                                     1                                                                    1B                                                                                     2 #STR20##                                                           ______________________________________                                    

What is claimed is:
 1. A compound of the formula ##STR21## wherein A isC₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, C₃ -C₇ cycloalkyl, substitutedC₃ -C₇ cycloalkyl, C₃ -C₆ alkenyl, substituted C₃ -C₆ alkenyl, C₃ -C₆alkynyl, substituted C₃ -C₆ alkynyl, C₁ -C₆ alkoxy, or C₀ -C₅alkyl-S(O)_(n) -C₀ -C₅ alkyl, C₀ -C₅ alkyl-O-C₀ -C₅ alkyl, C₀ -C₅alkyl-NR₁₈ -C₀ -C₅ alkyl where R₁₈ and the C₀ -C₅ alkyl can be joined toform a ring, ##STR22## or a single bond; R₀ is hydrogen; C₁ -C₆ alkyl,substituted C₁ -C₆ alkyl, wherein the substituents are as defined below;aryl, substituted aryl, aralkyl or substituted aralkyl, wherein thesubstituents are as defined for R₃, R₄ and R₅ ; ##STR23## wherein: Y isB, C or a bond;B is O, S(O)_(n), C(O), NR₁₈ or C(R₁₁ R₁₂)_(p) C isB(CH₂)_(p) --; R₂ is hydrogen, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl,aralkyl, substituted aralkyl, aryl, substituted aryl, alkyl --OR₁₁, C₁-C₆ (NR₁₁ R₁₂), C₁ -C₆ (CONR₁₁ R₁₂) or C(NR₁₁ R₁₂)NH; R₂ and A takentogether form a ring of 5-7 atoms; R₃, R₄ and R₅ are independentlyhydrogen, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, C₂ -C₆ alkenyl,substituted C₂ -C₆ alkenyl, CN, nitro, C₁ -C₃ perfluoroalkyl, C₁ -C₃perfluoroalkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl,R₁₁ O(CH₂)_(p) --, R₁₁ C(O)O(CH₂)_(p) --, R₁₁ OC(O)(CH₂)_(p) --,--(CH₂)_(p) S(O)_(n) R₁₇, --(CH₂)_(p) C(O)NR₁₁ R₁₂ or halogen; whereinR₁₇ is hydrogen, C₁ -C₆ alkyl, C₁ -C₃ perfluoroalkyl, aryl orsubstituted aryl; R₃ and R₄ taken together form a carbocyclic ring of3-7 carbon atoms or a heterocyclic ring containing 1-3 heteroatomsselected from N, O and S; R₆ is hydrogen, C₁ -C₆ alkyl, substituted C₁-C₆ alkyl, aryl, substituted aryl, C₁ -C₃ perfluoroalkyl, CN, NO₂,halogen, R₁₁ O(CH₂)_(p) --, NR₁₂ C(O)R₁₁, NR₁₂ C(O)NR₁₁ R₁₂ or SO_(n)R₁₁ ; R₇ is hydrogen, C₁ -C₆ alkyl, or substituted C₁ -C₆ alkyl, unlessX is hydrogen or halogen, then R₇ is absent; R₈ is hydrogen, C(O)OR₉,C(O)NR₁₁ R₁₂, NR₁₁ R₁₂, C(O)R₁₁, NR₁₂ C(O)R₁₁, NR₁₂ C(O)NR₁₁ R₁₂, NR₁₂S(O)₂ R₁₁, NR₁₂ S(O)₂ NR₁₁ R₁₂, OC(O)R₁₁, OC(O)NR₁₁ R₁₂, OR₁₁, SO_(n)R₁₁, S(O)_(n) NR₁₁ R₁₂, C₁ -C₆ alkyl or substituted C₁ -C₆ alkyl, unlessX is hydrogen or halogen, then R₈ is absent; or R₇ and R₈ taken togetherform a carbocyclic ring of 3-7 atoms; R₉ and R_(9a) are independentlyhydrogen, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl; aryl or substitutedaryl, aralkyl or substituted aralkyl when m≠0; or R₉ and R_(9a) takentogether form a carbocyclic ring of 3-7 atoms or ##STR24## when m≠0; R₉and A taken together form a heterocyclic ring containing 3-7 carbonatoms and one or more heteroatoms when m≠0; or R₁₀ and R_(10a) areindependently hydrogen, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, aryl,substituted aryl, aralkyl or substituted aralkyl; or R₁₀ and R_(10a)taken together form a carbocyclic ring of 3-7 atoms or ##STR25## R₉ andR₁₀ taken together form a carbocyclic ring of 3-7 carbon atoms or aheterocyclic ring containing one or more heteroatoms when m≠0; or R₉ andR₂ taken together form a heterocyclic ring containing 3-7 carbon atomsand one or more heteroatoms when m≠0; or R₁₀ and R₂ taken together forma heterocyclic ring containing 3-7 carbon atoms and one or moreheteroatoms; R₁₀ and A taken together form a heterocyclic ringcontaining 3-7 carbon atoms and one or more heteroatoms; or R₁₁ and R₁₂are independently hydrogen, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl,aryl, substituted aryl, aralkyl, substituted aralkyl, a carbocyclic ringof 3-7 atoms or a substituted carbocyclic ring containing 3-7 atoms; R₁₁and R₁₂ taken together can form an optionally substituted ring of 3-7atoms; R₁₃ is hydrogen, OH, NR₇ R₈, NR₁₁ SO₂ (C₁ -C₆ alkyl), NR₁₁ SO₂(substituted C₁ -C₆ alkyl), NR₁₁ SO₂ (aryl), NR₁₁ SO₂ (substitutedaryl), NR₁₁ SO₂ (C₁ -C₃ perfluoroalkyl); SO₂ NR₁₁ (C₁ -C₆ alkyl), SO₂NR₁₁ (substituted C₁ -C₆ alkyl), SO₂ NR₁₁ (aryl), SO₂ NR₁₁ (substitutedaryl), SO₂ NR₁₁ (C₁ -C₃ perfluoroalkyl); SO₂ NR₁₁ (C(O)C₁ -C₆ alkyl);SO₂ NR₁₁ (C(O)-substituted C₁ -C₆ alkyl); SO₂ NR₁₁ (C(O)-aryl); SO₂ NR₁₁(C(O)-substituted aryl); S(O)_(n) (C₁ -C₆ alkyl); S(O)_(n) (substitutedC₁ -C₆ alkyl), S(O)_(n) (aryl), S(O)_(n) (substituted aryl), C₁ -C₃perfluoroalkyl, C₁ -C₃ perfluoroalkoxy, C₁ -C₆ alkoxy, substituted C₁-C₆ alkoxy, COOH, halogen, NO₂ or CN; R₁₄ and R₁₅ are independentlyhydrogen, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, C₂ -C₆ alkenyl,substituted C₂ -C₆ alkenyl, CN, nitro, C₁ -C₃ perfluoroalkyl, C₁ -C₃perfluoroalkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl,R₁₁ O(CH₂)_(p) --, R₁₁ C(O)O(CH₂)_(p) --, R₁₁ OC(O)(CH₂)_(p) --,--(CH₂)_(p) S(O)_(n) R₁₇, --(CH₂)_(p) C(O)NR₁₁ R₁₂ or halogen; whereinR₁₇ is hydrogen, C₁ -C₆ alkyl, C₁ -C₃ perfluoroalkyl, aryl orsubstituted aryl; R₁₆ is hydrogen, C₁ -C₆ alkyl, substituted C₁ -C₆alkyl, or N(R₁₁ R₁₂); R₁₈ is hydrogen, C₁ -C₆ alkyl, substituted C₁ -C₆alkyl, C(O)OR₉, C(O)NR₁₁ R₁₂, C(O)R₁₁, S(O)_(n) R₁₁ ; X is hydrogen,halogen, N, O, S(O)_(n), C(O), (CR₁₁ R₁₂)_(p) ; C₂ -C₆ alkenyl,substituted C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, or substituted C₂ -C₆alkynyl; when X is hydrogen or halogen, R₇ and R₈ are absent; when X isO, S(O)_(n), C(O), or CR₁₁ R₁₂ only R₇ or R₈ is possible; m is 0-3; n is0-2; p is 0-4; andthe alkyl, cycloalkyl, alkenyl and alkynylsubstituents are selected from C₁ -C₆ alkyl, C₃ -C₇ cycloalkyl, aryl,substituted aryl, aralkyl, substituted aralkyl, hydroxy, oxo, cyano, C₁-C₆ alkoxy, fluoro, C(O)OR₁₁, aryl C₁ -C₃ alkoxy, substituted aryl C₁-C₃ alkoxy, and the aryl substituents are as defined for R₃, R₄ and R₅ ;or a pharmaceutically acceptable addition salt and/or hydrate thereof,or where applicable, a geometric or optical isomer or racemic mixturethereof.
 2. The compound according to claim 1 of the formula ##STR26##or a pharmaceutically acceptable addition salt and/or hydrate thereof,or where applicable, a geometric or optical isomer or racemic mixturethereof,wherein A and R₁ are as indicated in the following table:

    ______________________________________                                        Ex. #                                                                         (A)-R.sub.1                                                                   ______________________________________                                        1A                                                                                    3 #STR27##                                                            1B                                                                                    4 #STR28##                                                            1C                                                                                    5 #STR29##                                                            ______________________________________                                    


3. A pharmaceutical composition which comprises an effective amount of acompound as defined in claim 1 and a pharmaceutically acceptable carriertherefor.
 4. A method for antagonizing gonadotropin-releasing hormone ina subject in need thereof which comprises administering to said subjectan effective amount of a compound as defined in claim 1 to a subjectsuffering from a gonadotropin-releasing hormone derived disorder.
 5. Amethod according to claim 4 wherein the gonadotropin-releasing hormonederived disorder is a sex-hormone related condition.
 6. A methodaccording to claim 4 wherein the gonadotropin-releasing hormone deriveddisorder is a sex hormone dependent cancer, benign prostatic hypertropyor myoma of the uterus.
 7. A method according to claim 6 wherein the sexhormone dependent cancer is selected from the group consisting ofprostatic cancer, uterine cancer, breast cancer and pituitarygonadotrophe adenomas.
 8. A method according to claim 5 wherein the sexhormone related condition is selected from the group consisting ofendometriosis, polycystic ovarian disease, uterine fibroids andprecocious puberty.
 9. A method for preventing pregnancy in a subject inneed thereof which comprises administering an effective amount of acompound as defined in claim
 1. 10. A method for treating lupuserythematosis in a subject in need thereof which comprises administeringto said subject an effective amount of a compound as defined in claim 1.11. A method for treating irritable bowel syndrome in a subject in needthereof which comprises administering to said subject an effectiveamount of a compound as defined in claim
 1. 12. A method for treatingpremenstrual syndrome in a subject in need thereof which comprisesadministering to said subject an effective amount of a compound asdefined in claim
 1. 13. A method for treating hirsutism in a subject inneed thereof which comprises administering to said subject an effectiveamount of a compound as defined in claim
 1. 14. A method for treatingshort stature or a growth hormone deficiency in a subject in needthereof which comprises administering to said subject an effectiveamount of a compound which stimulates the endogenous production orrelease of growth hormone and an effective amount of a compound asdefined in claim
 1. 15. A method for treating sleep disorders in asubject in need thereof which comprises administering to said subject aneffective amount of a compound as defined in claim
 1. 16. The method ofclaim 15 wherein the sleep disorder is sleep apnea.
 17. A mammographicmethod in which the image on the mammographic film has enhancedreadability relative to a mammogram effected in the absence of themethod, which comprises administering to a premenopausal woman aneffective amount of a compound as defined in claim
 1. 18. Apharmaceutical composition which comprises an inert carrier and aneffective amount of a compound which stimulates the endogenousproduction or release of growth hormone in combination with a compoundas defined in claim
 1. 19. A pharmaceutical composition made bycombining the compound of claim 1 and a pharmaceutically acceptablecarrier therefor.
 20. A process for making a pharmaceutical compositioncomprising combining a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 21. Pharmaceutical therapy comprisingco-administration of a compound having luteinizing hormone releasinghormone activity with a compound of claim
 1. 22. The therapy of claim 21wherein the compound having luteinizing hormone releasing hormoneactivity is a peptide compound.
 23. The therapy of claim 22 wherein thepeptide compound is a natural hormone or an analog thereof.
 24. Thetherapy of claim 22 wherein the peptide compound is a compound selectedfrom the group consisting of leuprorelin, gonadorelin, buserelin,triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterelin andrecirelin.
 25. Pharmaceutical combination therapy comprising a compoundhaving luteinizing hormone releasing hormone activity in combinationwith a compound of claim
 1. 26. The therapy of claim 25 wherein thecompound having luteinizing hormone releasing hormone activity is apeptide compound.
 27. The therapy of claim 26 wherein the peptidecompound is a natural hormone or an analog thereof.
 28. The therapy ofclaim 26 wherein the peptide compound is a compound selected from thegroup consisting of leuprorelin, gonadorelin, buserelin, triptorelin,goserelin, nafarelin, histrelin, deslorelin, meterelin and recirelin.